CCN family of proteins: critical modulators of the tumor cell microenvironment

Abstract

The CCN family of proteins consisting of CCN1 (Cyr61), CCN2 (CTGF), CCN3 (NOV), CCN4 (WISP-1), CCN5 (WISP-2) and CCN6 (WISP-3) are considered matricellular proteins operating essentially in the extracellular microenvironment between cells. Evidence has also been gradually building since their first discovery of additional intracellular roles although the major activity is triggered at the cell membrane. The proteins consist of 4 motifs, a signal peptide (for secretion} followed consecutively by the IGFBP, VWC, TSP1 and CT (C-terminal cysteine knot domain) motifs, which signify their potential binding partners and functional connections to a variety of key regulators of physiological processes. With respect to cancer it is now clear that, whereas certain members can facilitate tumor behavior and progression, others can competitively counter the process. It is therefore clear that the net outcome of biological interactions in the matrix and what gets signaled or inhibited can be a function of the interplay of these CCN 1-6 proteins. Because the CCN proteins further interact with other key proteins, like growth factors in the matrix, the balance is not only important but can vary dynamically with the physiological states of tumor cells and the surrounding normal cells. The tumor niche with its many cell players has surfaced as a critical determinant of tumor behavior, invasiveness, and metastasis. It is in this context that CCN proteins should be investigated with the potential of being recognized and validated for future therapeutic approaches.

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

“…Notably, miR-205-5p as well as miR-200/141 and 429 were anti-correlated (rho ≤ −0.4) to the EMT-related transcription factors ZEB1 and ZEB2 (Figures 7C and S7C). Other anti-correlated miR-205-5p targets potentially related to EMT included connective tissue growth factor (CTGF), cysteine-rich protein 61 (CYR61) (Lau, 2016; Thakur and Mishra, 2016; Yeger and Perbal, 2016), and the inositol phosphatase INPPL1 (SHIP2), which is involved in extracellular matrix (ECM) degradation and carcinoma invasiveness (Rajadurai et al, 2016). The EMT-related mRNAs ZEB2, CTGF, and CYR61 were observed to cluster together above in a branch of mRNA C1 with LUSC and C6 with HNSC that overlap miRNA C2 and C3 with decreased expression of these miRs (Figure S7A, mRNA track).…”

Tspan15 Is a New Stemness‐Related Marker in Hepatocellular Carcinoma

“…Data reported in recent years provides compelling evidence that CTGF/CCN2 is a key factor in development of hepatic fibrosis and cancer. [51,53,[65][66][67] High level of CTGF/CCN2 protein was found in KRT19 positive HCC supporting a role for CTGF/CCN2 in hepatic progenitor cells activation during carcinogenesis. [68,69] The role of Tspan15 in cell proliferation is highlighted by our study.…”

“…All six proteins are highly evolutionarily conserved and share substantial homology with each other. Structurally, the proteins are organized in four individual cysteine‐rich modules containing an insulin‐like growth factor binding domain, a von Willebrand factor type C, a thrombospondin type 1 repeat, and a cysteine knot motif . A complex picture has emerged regarding the manner in which cell function is regulated by CCN proteins.…”

“…Structurally, the proteins are organized in four individual cysteine-rich modules containing an insulin-like growth factor binding domain, a von Willebrand factor type C, a thrombospondin type 1 repeat, and a cysteine knot motif. [65,66] A complex picture has emerged regarding the manner in which cell function is regulated by CCN proteins. This derives from key observations demonstrating that they are heparin-binding and sequestered with heparan sulfate proteoglycans (HSPG) on cell surfaces and in extracellular matrix (ECM).…”

Clinical relevance of Cyr61 expression in patients with hormone-dependent breast cancer

“…with hormone-dependent breast cancer including angiogenesis (7,10); however, the alteration of Cyr61 expression has been demonstrated to be associated with a number of pathologies (11)(12)(13), including malignant neoplasms (14,15). In previous studies by our group, Cyr61 expression profiling in BC and its functional expression regulation was examined (16,17) demonstrating a stage-dependent induction of Cyr61 in BC tumorigenesis and hypoxia-induced alternative splicing of Cyr61 in tumor cells.…”